Human SLAMF1 (signaling-lymphocytic-activation-molecule-family1, CD150) is a self-ligand adhesion/co-stimulatory molecule wich belongs to a family of 9 receptors. SLAMF1 is also a microbial sensor, as it regulates Gram- bacterial phagosome functions through an ubiquitous cellular autophagic machinery and serves as a receptor for Measles virus.
In this work, we investigated expression and function of SLAMF1 in chronic lymphocytic leukemia (CLL) cells. Results indicate that expression of SLAMF1 is lost in a subset of patients with chronic lymphocytic leukemia characterized by an aggressive form of the disease, with shorter time to first treatment (median 2.2 years in SLAMF1- vs 7.6 in SLAMF1+ patients, P=.001) and overall survival (77.5% survival rate at 10 years in SLAMF1- vs 94.7% years in SLAMF1+ patients, P=.036). Consistently, SLAMF1low CLL patients are characterized by clinical or molecular markers of a more aggressive disease.
Stable silencing of SLAMF1 in the CLL-like Mec-1 cell line (constitutively SLAMF1+) modulated pathways related to cell migration, cytoskeletal organization and intracellular vesicle formation/recirculation. Decreased expression of CXCR3 and an increased expression of CXCR4, CD38 and CD44 were maintained at the molecular level, likely explaining why SLAMF1- cells show enhanced chemotactic responses to CXCL12. This phenotype was confirmed in primary cells, by comparing a cohorts of SLAMF1high to one of SLAMF1low patients.
Gene expression profiling also indicates profound modulation of pathways connected with vesicle formation and recirculation. Consistently, cross-linking of SLAMF1 with an agonisic mAb in primary cells and in the Mec-1 cell line enhanced the generation of autophagic vesicles and their fusion with the lysosomes. Ligation of SLAMF1 with this agonistic monoclonal antibody promoted the autophagic flux, by increasing accumulation of reactive oxygen species (ROS) and inducing phosphorylation of p38, JNK1/2 and bcl-2. The direct consequence was the formation of the autophagy macro-complex containing SLAMF1, the scaffold protein beclin1 and the enzyme Vps34. In agreement with the observation that many drugs used in CLL have autophagy-mediated effects, including fludarabine and the BH3 mimetic ABT-737, SLAMF1-silenced Mec-1 cells or SLAMF1low primary CLL cells were resistant to treatment with both agents.
These results indicate that SLAMF1 plays as a critical role in CLL homeostasis. Loss of SLAMF1 expression modulates genetic pathways that regulate chemotaxis and autophagy and that potentially affect drug responses, thus providing a likely explanation for the unfavorable clinical outcome experienced by this patient subset. Restoring SLAMF1 expression in CLL cells would therefore be of therapeutic value for patients with aggressive CLL.
Gaidano:Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory boards; Celgene: Research Funding.
Asterisk with author names denotes non-ASH members.